Novel N-bis-azacyclopentan-2-onyl alkanes

ABSTRACT

There is disclosed an improved method for topically administering a physiologically active agent to a human or animal by dissolving an effective amount of the agent in a carrier containing suitable amounts of N-bis-azacyclopentan-2-onyl alkanes, as defined herein, and contacting the skin or other membranes of the human or animal with the resulting composition, whereby penetration of the skin or membranes is enhanced.

BACKGROUND OF THE INVENTION

Many physiologically active agents are best applied topically to obtaindesirable results. Topical application, as contrasted to systemicapplication, largely avoids side effects of the agents and permits highlocal concentrations of the agents.

The greatest problem in applying physiologically active agents topicallyis that the skin is such an effective barrier to penetration. Theepidermis of the skin has an exterior layer of dead cells called thestratum corneum which is tightly compacted and oily and which providesan effective barrier against gaseous, solid or liquid chemical agents,whether used alone or in water or oil solutions. If a physiologicallyactive agent penetrates the stratum corneum, it can readily pass throughthe basal layer of the epidermis and into the dermis.

Although the effectiveness of the stratum corneum as a barrier providesgreat protection, it also frustrates efforts to apply beneficial agentsdirectly to local areas of the body. The inability of physiologicallyactive agents to penentrate the stratum corneum prevents their effectiveuse to treat such conditions as inflamation, acne, psoriasis, herpessimplex, eczema, infections due to fungus, virus or othermicroorganisms, or other disorders or conditions of the skin or mucuousmembranes, or of conditions beneath the exterior surface of the skin ormucous membranes. The stratum corneum also prevents the skin fromabsorbing and retaining cosmetic-type materials such as sunscreens,perfumes, mosquito repellants and the like.

Physiologically active agents may be applied to locally affected partsof the body through the vehicle system described herein. Vehicles suchas USP cold cream, ethanol and various ointments, oils, solvents, andemulsions have been used heretofore to apply physiologically activeingredients locally. Most such vehicles are not effective to carrysignificant amounts of physiologically active agents through the skin.One such vehicle is dimethyl sulfoxide, which is described in U.S. Pat.No. 3,551,554. In this description, the term "animal" includes humanbeings as well as other forms of animal life, and especiallydomesticated animals and pets.

SUMMARY OF THE INVENTION

This invention is a method for carrying physiologically active agentsthrough body membranes such as skin and for retaining these agents inbody tissues. The invention also relates to compositions for use in themethod. More specifically, the invention relates to a method fortopically adminstering a physiologically active agent to a human oranimal comprising administering topically to a human or animal aneffective amount of a composition containing the agent and an effective,non-toxic amount of a compound having the structural formula ##SPC1##

Wherein R is H or a lower alkyl group having 1-4 carbon atoms and n is apositive integer from 1-18 and preferably 3-10. In a preferredembodiment, R is H and n is 3.

The invention also relates to novel compounds having the foregoingstructural formula.

It has been found that the physiologically active agents are carriedthrough body membranes by the claimed vehicles and are retained in bodytissues.

DETAILED DESCRIPTION OF THE INVENTION

Referring more particularly to the above structural formula, the carbonchain formed between the azacyclopentan-2-one rings may be straight orbranched. n is a positive integer from 1-18 and preferably from 3-10. Ris H or an alkyl group having 1-4 carbon atoms.

The compounds described herein are useful in research relating topercutaneous penetration, i.e. the compounds of the present inventionenhance percutaneous absorption of topically administered chemicalagents, e.g. drugs, perfumes, dyes, insect repellants, etc. Thecompounds may be used to enhance percutaneous absorption of chemicalagents at concentrations from about 1 to about 95 and preferably about 5to about 25 percent by weight of a topical composition containing thechemical agent.

The compounds covered by the general formula above may be prepared byheating two moles or a slight excess of γ-butyrolactone with adiaminoalkane for 10 to 24 hours at 170°-250° C to obtain theN-bis-azacyclopentan-2-onyl alkane. This method is outlined below:##SPC2##

where n has the same meaning as before.

In an alternate method, azacyclopentan-2-one is treated with adihaloalkane or an alkyldimesylate in the presence of a base. Thepreferred base is sodium hydride. The reaction is carried out underanhydrous condition in a hydrocarbon solvent, for example, dry toluene,at reflux temperature for a period of 20 to 72 hours in an inertatmosphere, for example, nitrogen. This method is outlined below:##SPC3##

In the foregoing outline, X represents the halide or mesylate group.

In a second alternate method, the azacyclopentan-2-one may be treatedwith a haloalkanol in the presence of a base. The hydroxy group of theproduct may then be converted to a halide or a mesylate by known methodsand treated under similar conditions as described above with anothermolecule or azacyclopentan-2-one to obtain the final product. Thereaction involving the dihalo compound is preferred.

The process of this invention may find use with many physiologicallyactive agents which are soluble in the vehicles disclosed.

Fungistatic and fungicidal agents such as, for example, thiabendazole,chloroxine, amphotericin, candicidin, fungimycin, nystatin,chlordantoin, clotrimazole, ethonam nitrate, miconazole nitrate,pyrrolnitrin, salicylic acid, fezatione, ticlatone, tolnaftate,triacetin and zinc and sodium pyrithione may be dissolved in thevehicles described herein and topically applied to affected areas of theskin. For example, fungistatic or fungicidal agents so applied arecarried through the stratum corneum, and thereby successfully treatfungus-caused skin problems. These agents, thus applied, not onlypenetrate more quickly than when applied in the vehicles of the priorart, but additionally enter the animal tissue in higher concentrationsand are retained for substantially longer time periods whereby a farmore successful treatment is effected.

For example, the method of this invention may also be employed in thetreatment of fungus infections on the skin caused by candida anddermatophytes which cause athletes foot or ringworm, by dissolvingthiabendazole or similar antifungal agents in one of the vehicles andapplying it to the affected area.

The invention is also useful in treating skin problems, such as forexample, herpes simplex, which may be treated by a solution ofiododeoxyuridine dissolved in one of the vehicles, or such problems aswarts which may be treated with agents such as podophylline dissolved inone of the vehicles. Skin problems such as psoriasis may be treated bytopical application of a solution of a conventional topical steroid inone of the vehicles or by treatment with theophylline or antagonists ofβ-adrenergic blockers such as isoproterenol in one of the vehicles.Scalp conditions such as alopecia areata may be treated more effectivelyby applying steroids such as triamcinolone acetonide dissolved in one ofthe vehicles of this invention directly to the scalp.

The present invention is also useful for treating mild eczema, forexample, by applying a solution of fluocinolone acetonide or itsderivatives; hydrocortisone, triamcinolone acetonide, indomethacin, orphenylbutazone dissolved in one of the vehicles to the affected area.

Examples of other physiologically active steroids which may be used withthe vehicles include corticosteroids such as, for example, cortisone,cortodoxone, flucetonide, fludrocortisone, difluorsone diacetate,flurandrenolone acetonide, medrysone, amcinafel, amcinafide,betamethasone and its esters, chloroprednisone, clocortelone,descinolone, desonide dexamethasone, dichlorisone, difluprednate,fluchloronide, flumethasone, flunisolide, fluocinonide, flucortolone,fluoromethalone, fluperolone, fluprednisolone, meprednisone,methylmeprednisolone, paramethasone, prednisolone and prednisone.

This invention is also useful in antibacterial chemotherapy, e.g., inthe treatment of skin conditions involving pathogenic bacteria. Typicalantibacterial agents which may be used in this invention includesulfonomides, penicillins, cephalosporins, penicillinase, erythromycins,lincomycins, vancomycins, tetracyclines, chloramphenicols,streptomycins, etc. Typical examples of the foregoing includeerythromycin, erythromycin ethyl carbonate, erythromycin estolate,erythromycin glucepate, erythromycin ethylsuccinate, erythromycinlactobionate, lincomycin, clindamycin, tetracycline, chlortetracycline,demeclocycline, doxycycline, methacycline, oxytetracycline, minocycline,etc.

This invention is also useful in protecting ultra-sensitive skin or evennormally sensitive skin from damage or discomfort due to sunburn. Thus,dermatitis actinica may be avoided by application of a sunscreen, suchas para-aminobenzoic acid or its well-known derivatives dissolved in oneof the vehicles, to skin surfaces that are to be exposed to the sun; andthe protective para-aminobenzoic acid or its derivatives will be carriedinto the stratum corneum more successfully and will therefore beretained even when exposed to water or washing for a substantiallylonger period of time than when applied to the skin in conventionalvehicles. This invention is particularly useful for ordinary suntanlotions used in activities involving swimming because the ultravioletscreening ingredients in the carriers of the prior art are washed offthe skin when it is immersed in water.

This invention may also find use in treating scar tissue by applyingagents which soften collagen, such as aminoproprionitrile orpenicillamine dissolved in one of the vehicles of this inventiontopically to the scar tissue.

Agents normally applied as eye drops, ear drops, or nose drops are moreeffective when dissolved in the vehicles of this invention.

Agents used in diagnosis may be used more effectively when applieddissolved in one of the vehicles of this invention. Patch tests todiagnose allergies may be effected promptly without scratching the skinor covering the area subjected to an allergen when the allergens areapplied in one of the vehicles of this invention.

This invention is also useful for topical application of cosmetic oresthetic agents. For example, compounds such as melanin-stimulatinghormone (MSH) or dihydroxy acetone and the like are more effectivelyapplied to skin to simulate a suntan when they are dissolved in one ofthe vehicles of this invention. The agent is carried into the skin morequickly and in greater quantity when applied in accordance with thisinvention. Hair dyes also penetrate more completely and effectively whendissolved in one of the vehicles of this invention.

The effectiveness of such topically applied materials as insectrepellants or fragrances, such as perfumes and colognes, can beprolonged when such agents are applied dissolved in one of the vehiclesof this invention.

It is to be emphasized that the foregoing are simply examples ofphysiologically active agents including therapeutic and cosmetic agentshaving known effects for known conditions, which may be used moreeffectively for their known properties in accordance with thisinvention.

In addition, the vehicles of the present invention may also be used toproduce therapeutic effects which were not previously known. That is, byuse of the vehicles described herein, therapeutic effects heretofore notknown can be achieved.

As an example of the foregoing, griseofulvin is known as the treatmentof choice for fungus infections of the skin and nails. Heretofore, themanner of delivery of griseofulvin has been oral. However, it has longbeen known that oral treatment is not preferred because of side effectsresulting from saturation of the entire body with griseofulvin and thefact that only the outer layers of affected skin need to be treated.Therefore, because fungal infections are generally infections of theskin and nails, it would be advantageous to utilize griseofulvintopically. However, despite a long-felt need for a topical griseofulvin,griseofulvin has been used orally to treat topical fungus conditionsbecause there was not heretofore known any formulation which could bedelivered topically which would cause sufficient retention ofgriseofulvin in the skin to be useful therapeutically.

However, it has now been discovered that griseofulvin, in a range oftherapeutic concentrations between about 0.1% and about 10% may be usedeffectively topically if combined with one of the vehicles describedherein.

As a further example, acne is the name commonly applied to anyinflammatory disease of the sebaceous glands; also acne vulgaris. Themicroorganism typically responsible for the acne infection isCorynebacterium acnes. Various therapeutic methods for treating acnehave been attempted including topical antibacterials, e.g.hexachlorophene, and systemic antibiotics such as tetracycline. Whilethe systemic antibiotic treatment are known to be partially effective,the topical treatments are generally not effective.

It has long been known that systemic treatment of acne is not preferredbecause of side effects resulting from saturation of the entire bodywith antibiotics and the fact that only the affected skin need bytreated. However, despite a long-felt need for a topical treatment foracne, antibiotics generally have been used only systemically to treatacne because there was not heretofore known an anti-bacterialformulation which could be used topically which would be effectivetherapeutically in the treatment of acne. However, it has now beendiscovered that antibiotics, especially those of the lincomycin anderythryomycin families of antibiotics, may be used in the treatment ofacne topically if combined with one of the vehicles described herein.

The antibiotics composition so applied is carried into and through theepidermis and deeper layers of the skin as well as into follicles andcomedones (sebum-plugged follicles which contain C. acnes) intherapeutically effective amounts and thereby successfully may be usedto temporarily eliminate the signs and symptoms of acne.

The term "physiologically active agent" is used herein to refer to abroad class of useful chemical and therapeutic agents includingphysiologically active steroids, antibiotics, antifungal agents,antibacterial agents, antineoplastic agents, allergens, antihistamicagents, anti-inflammatory agents, ultraviolet screening agents,diagnostic agents, perfumes, insect repellants, hair dyes, etc.

Dosage forms for topical application may include solution nasal sprays,lotions, ointments, creams, gels suppositories, sprays, aerosols and thelike. Typical inert carrier which make up the foregoing dosage formsinclude water, acetone, isopropyl alcohol, freons, ethyl alcohol,polyvinyl pyrrolidone, propylene glycol, fragrances, gel-producingmaterials, mineral oil, stearyl alcohol, stearic acid, spermaceti,sorbitan monooleate, "Polysorbates", "Tweens," sorbital,methylcellulose, etc.

The amount of the composition, and thus of the physiologically activeagent therein, to be administered will obviously be an effective amountfor the desired result expected therefrom. This, of course, will beascertained by the ordinary skill of the practitioner. Due to enhancedactivity which is achieved, the dosage of agent may often be decreasedfrom that generally applicable. In accordance with the usual prudentformulating practices, a dosage near the lower end of the useful rangeof the particular agent may be employed initially and the dosageincreased as indicated from the observed response, as in the routineprocedure of the physician.

The examples which follow illustrate the compositions of the presentinvention. Temperatures are given in degrees Centigrade.

EXAMPLE 1 Preparation of N-bis-1,6-(azacyclopentan-2-onyl)-hexane

21.66 g (0.25M) of 1,6-diaminohexane and 11.62 g (0.1 mole) ofγ-butyrolactone were heated overnight at 170°-180° C. The reactionmixture was cooled whereupon it solidified. Excess γ-butyrolactone wasremoved at reduced pressure and the hot liquid residue was poured into acrystallization dish where it immediately solidified. This was taken inchloroform and filtered to obtain 22.5 g (89%) of the product.(Alternatively, the excess γ-butyrolactone may be removed by washingwith an organic solvent in which the product is insoluble instead ofdistilling it out at reduced pressure).

M.P. 100°-103°. NMR (D₂ O) 1.3 - 2.8 δ complex; 3.3 - 4.1 δ complex,

EXAMPLE 2 Preparation of N-bis-1,3-(azacyclopentan-2-onyl)-propane

A mixture of 11.0 g of 5% sodium hydride-mineral oil suspension and 105ml of dry toluene (distilled over CaH₂) was stirred under nitrogenatmosphere as 20 g (0.235 mole) of azacyclopentane-2-one was addeddropwise over a period of 7 hours. After the addition was complete, themixture was refluxed for 1 hour and then 22.3 g (0.11 mole) of1,3-dibromopropane was added dropwise over three hours. The refluxingwas continued during the addition and for 72 hours thereafter. Themixture was cooled and filtered through celite. The solvent was removedto yield a residue consisting of two phases. The lower phase was removedand distilled at 170°-172°/0.01 mm. GC analysis showed a single peak andthe N.M.R. spectrum was consistent with the expected product. Thismaterial was redistilled at 179°-180°/0.03 mm to yield 8.2 g of product.

G.C. one peak on 5% SE30 column. I.R. (liquid film): 3500, 2938, 2878,1685, 1498, 1465, 1425, 1380, 1365, 1330, 1315(s), 1290, 1259, 1229,1170, 1110, 1065, 998, 930, 852, 750, 735, 650 cms⁻ ¹. N.M.R. (CDCl₃ +TMS) 1.5 - 2.7 δ ; 3.2 - 3.9 δ .

EXAMPLE 3

The following solution formulation is prepared.

    ______________________________________                                                             Solution (%)                                             Griseofulvin           1                                                      N-bis-1,3-(azacyclopentan-2-                                                                         5                                                      onyl)-propane                                                                 Isopropyl myristate    5                                                      Fragrance              0.1                                                    Ethanol qs. ad                                                                ______________________________________                                    

This formulation is effective in the treatment of fungus infections.

EXAMPLE 4

An aerosol form of the formulation of Example 3 is prepared by preparingthe following mixture:

    ______________________________________                                               Formulation    25%                                                            Freon.sup.1    75%                                                     ______________________________________                                         .sup.1 Freon is 75/25 Freon 114/12.                                      

EXAMPLE 5

The following cream formulation is prepared:

    ______________________________________                                                               %                                                      Clindamycin (base)       1.0                                                  Stearyl alcohol, U.S.P.  12.0                                                 Ethoxylated cholestrol   0.4                                                  Synthetic spermaceti     7.5                                                  Sorbitan monooleate      1.0                                                  Polysorbate 80, U.S.P.   3.0                                                  N-bis-1,3-(azacyclopentan-2-onyl)-                                                                     10.0                                                  propane                                                                      Sorbitol solution, U.S.P.                                                                              5.5                                                  Sodium citrate           0.5                                                  Chemoderm No. 844 Fragrance                                                                            0.2                                                  Purified water qs. ad                                                         ______________________________________                                    

This formulation is effective in the treatment of acne.

EXAMPLE 6

The following solution formulations are prepared:

    ______________________________________                                                         A(%)     B(%)                                                Clindamycin base   --         1.0                                             Clindamycin phosphate acid                                                                       1.3        --                                              Sodium hydroxide   0.077      --                                              1.0 Molar hydrochloric acid                                                                      --         2.27                                            Disodium edetate.2H.sub.2 O                                                                      0.0033     0.0033                                          Fragrances         0.5        0.5                                             N-bis-1,6-(azacyclopentan-2-onyl)-                                                               15.0       15.0                                             hexane                                                                       Purified water     20.0       17.73                                           Isopropanol qs. ad.                                                           ______________________________________                                    

These solutions are effective for the treatment of acne in humans.

EXAMPLE 7

The following solution formulation is prepared:

    ______________________________________                                                               %                                                      Neomycin sulfate         0.5                                                  Lidocaine                0.5                                                  Hydrocortisone           0.25                                                 N-bis-1,4-(azacyclopentan-2-onyl)-                                                                     25.0                                                  butane                                                                       Propylene glycol qs. ad.                                                      ______________________________________                                    

This solution is effective for the treatment of otitis in domesticanimals.

EXAMPLE 8

The following sunscreen emulsion is prepared:

    ______________________________________                                                               %                                                      p-amino benzoic acid     2.0                                                  Benzyl alcohol           0.5                                                  N-bis-1,5-(azacyclopentan-2-onyl)-                                                                     40.0                                                  pentane                                                                      Polyethylene glycol 400-MS                                                                             10.0                                                 Isopropyl lanolate       3.0                                                  Lantrol                  1.0                                                  Acetylated lanolin       0.5                                                  Isopropyl myristate      5.0                                                  Light mineral oil        8.0                                                  Cetyl alcohol            1.0                                                  Veegum                   1.0                                                  Propylene glycol         3.0                                                  Purified water qs. ad                                                         ______________________________________                                    

EXAMPLE 9

The following antineoplastic solution is prepared:

    ______________________________________                                                               %                                                      5-Fluorouracil           5                                                    N-bis-1,3-(azacyclopentan-2-                                                   onyl)-propane           20                                                   Polyethylene glycol      5                                                    Purified water qs. ad                                                         ______________________________________                                    

EXAMPLE 10

The following insect repellant atomizing spray is prepared:

    ______________________________________                                                             %                                                        Diethyltoluamide       0.1                                                    N-bis-1,3-(azacyclopentan-                                                     2-onyl)-propane       10                                                     Ethanol qs. ad                                                                ______________________________________                                    

EXAMPLE 11

The following lotion formulation may be prepared containing about 0.001to 1 percent, with preferably 0.1 percent fluocinolone acetonide:

    ______________________________________                                                             %                                                        Fluocinolone acetonide                                                                             0.001 - 1                                                Cetyl alcohol        15                                                       Propylene glycol     10                                                       Sodium lauryl sulfate                                                                              15                                                       N-bis-1,3-(azacyclopantan-                                                     2-onyl)-propane     20                                                       Water qs. ad.                                                                 ______________________________________                                    

The steroid is dissolved in the vehicle and added to a stirred, coolingmelt of the other ingredients. The preparation is particularly usefulfor the treatment of inflammed dermatoses by topical application to theaffected skin area. The amount and frequency of application is inaccordance with standard practice for topical application of thissteroid. Penetration of the steroid into the inflammed tissue isenhanced and a therapeutic level is achieved more rapidly and sustainedfor longer duration than when the steroid is applied in conventionalformulations.

EXAMPLE 12

The percutaneous penetration of one of the claimed vehicles was comparedto a structurally related prior art vehicle by means of a diffusion cellusing excised hairless mouse skin as a membrane. Skin specimens wereobtained from male mice 14-16 weeks. Old test solution contained 2%8-Bromo-cyclic-adenosine monophosphate and 1-% phosphate buffer (0.1M;pH 6.2) and equimolar amounts of vehicle. The volume of test solutionapplied to the membrane was 0.5 Ml/cm². The results represent averagevalues obtained from 2-4 skin cells and are shown in Table 1 below.

                                      Table 1                                     __________________________________________________________________________           Penetration (hrs)                                                                       Flux    P.C.sup.3                                            Composition                                                                          25 50 75  (mole/cm.sup.2 /min)                                                                  (μcm/min)                                                                        P.R.sup.4                                      __________________________________________________________________________    A.sup.1                                                                               5 50 100 0.033   1.346 moderate                                       B.sup.2                                                                              10 65 120 0.037   1.510 moderate                                       __________________________________________________________________________     .sup.1 A: 40% 1-methyl-azacyclopentan-2-one in propylene                      .sup.2 B: Equimolar amounts of N-bis-1,3-azacyclopentan-2-onyl)-propane i     propylene glycol.                                                             .sup.3 PC: Permeability Constant.                                             .sup.4 PR: Penetration Rating                                            

I claim:
 1. A method for enhancing the penetration of physiologicallyactive agents through human and animal body skin and membranescomprising administering to a human or animal a composition comprisingan effective amount of said agent and a non-toxic, effective membranepenetrating amount of a compound having the formula ##SPC4##wherein R isselected from the group consisting of H and alkyl having 1-4 carbonatoms and n is a positive integer from 1-18.
 2. The method of claim 1wherein the physiologically active agent is an antibacterial agent. 3.The method of claim 2, wherein the antibacterial agent is an antibiotic.4. The method of claim 3 wherein the antibiotic is selected from thegroup consisting of lincomycin, clindamycin, erythromycin andpharmaceutically useful salts thereof.
 5. The method of claim 1 whereinthe physiologically active agent is a physiologically active steroid. 6.The method of claim 1 wherein the physiologically active agent is anantifungal agent.
 7. The method of claim 1 wherein the physiologicallyactive agent is iododeoxyuridine.
 8. The method of claim 1 wherein thephysiologically active agent is a sunscreen.
 9. The method of claim 8wherein the sunscreen is para-aminobenzoic acid or an active derivativethereof.
 10. The method of claim 1 wherein the physiologically activeagent is 5-fluorouracil.
 11. The method of claim 1 wherein thephysiologically active agent is an allergen.